Astrocytes, the most abundant non-neuronal cell type in the brain, have traditionally been thought of as passive supporters of neuronal circuits. However, in recent years, work from many groups has shown that astrocytes communicate bidirectionally with neurons. The consequence of neuron-astroglia signaling in modulating neural circuit function and behavior has been unclear, as have the specific mechanisms used by astrocytes to talk to downstream neurons. A new study in Science (PDF) by researchers in the Engert lab has identified a role for astrocytes in implementing feedforward inhibition over slow timescales and filled in critical molecular details in a biochemical pathway that astrocytes use to signal to neurons.
Fish that ‘give up’
Larval zebrafish exhibit an innate tendency to swim against the current. Alex Chen, a graduate student in Harvard’s Program in Neuroscience (PiN) and first author of the study, investigated this behavior. Working in the laboratories of Dr. Florian Engert in MCB and Dr. Misha Ahrens at the Howard Hughes Medical Institute’s Janelia Research Campus, Chen placed fish in virtual reality: when fish tried to swim by moving their tails, the researchers used a video projector to move a virtual world backwards, simulating forward motion. Of particular interest to Chen and colleagues was the fish’s behavior when its swims no longer worked to move it forward. To make the fish’s swims futile, the researchers withheld visual feedback in response to swim attempts. Previous work in the Ahrens lab had shown that under such conditions of ‘futility’ the fish will eventually cease all efforts, stop their swim behavior altogether and simply ‘give up’. It was further discovered that a population of neurons in the hindbrain induce this ‘giving up’ response by releasing the fight-or-flight neuromodulator norepinephrine in response to futile swims.
Remarkably, this futility signal does not act on other neurons but instead on astrocytes, which respond to norepinephrine through elevation of intracellular calcium. However, an important open question was how astroglial calcium signals are relayed to downstream neural circuits to inhibit swims, and Chen set out to investigate this mechanism.
Astroglia signal to neurons through ATP and adenosine
Hypothesizing that astroglia secreted a signal that could activate or inhibit neurons, Chen and Marc Duque Ramirez, a fellow PiN student and second author of the manuscript, performed whole-brain imaging of astroglial intracellular calcium and putative astrocyte-secreted transmitters during futility. They discovered that in response to futility-driven norepinephrine release, astrocytes release a molecule called adenosine triphosphate (ATP). While ATP is more widely known as the primary carrier of energy in all living things, it can also act as a signaling molecule between neurons. In this case, however, rather than acting on neurons directly, the ATP is first converted into adenosine by extracellular enzymes. Adenosine then drives inhibitory neurons in the hindbrain by activating A2 adenosine receptors. Interestingly, adenosine receptors are a target of caffeine, the active ingredient of coffee, and Chen and colleagues speculate that caffeine may exert some of its mood and energy-boosting effects through this astroglia-to-neuron pathway. By identifying this extracellular signaling pathway linking astrocytes to neurons, Chen and colleagues have elucidated one pathway through which astrocytes can influence neurons, with significant consequences for behavior. Companion papers published back-to-back from Thomas Papouin’s lab at Washington University in St. Louis and Marc Freeman’s lab at Oregon Health and Science University have identified similar pathways in mice and fruit flies, raising the possibility that the norepinephrine-astroglia-purinergic signaling motif, or NAP motif, may be an evolutionarily ancient pathway for switching brain and behavioral state.
